Hot melt extrusion processing parameters optimization

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The aim of this study was to demonstrate the impact of processing parameters of the hot-melt extrusion (HME) on the pharmaceutical formulation properties. Carbamazepine (CBZ) was selected as a model water-insoluble drug. It was incorporated into Soluplus®, which was used as the polymeric carrier, to produce a solid dispersion model system. The following HME-independent parameters were investigated at different levels: extrusion temperature, screw speed and screw configuration. Design of experiment (DOE) concept was applied to find the most significant factor with minimum numbers of experimental runs. A full two-level factorial design was applied to assess the main effects, parameter interactions and total error. The extrudates’ CBZ content and the in vitro dissolution rate were selected as response variables. Material properties, including melting point, glass transition, and thermal stability, and polymorphs changes were used to set the processing range. In addition, the extruder torque and pressure were used to find the simplest DOE model. Each change of the parameter showed a unique pattern of dissolution profile, indicating that processing parameters have an influence on formulation properties. A simple, novel and two-level factorial design was able to evaluate each parameter effect and find the optimized formulation. Screw configuration and extrusion temperature were the most affecting parameters in this study

FORMULATION AND CHARACTERIZATION OF FLUCONAZOLE LOADED OLIVE OIL NANOEMULSIONS

Present study was carried out to develop and evaluate olive oil based nano-emulsion for transdermal delivery of fluconazole, a bistriazole based antifungal agent with poor water solubility and lipophilicity. Olive oil, a natural non-irritating, non-toxic proposed permeation enhancer, is known to have some antifungal activity as well. Screening of common emulsifiers like Tweens (Tween 20, tween 60, tween 80), Spans (span 60, span 80), brij 35, puronic 127, and poloxamer 188 were done based on solubility of fluconazole in these surfactants followed by their efficiency to emulsify olive oil in water. Co-emulsifiers such as glycols (polyethylene glycol 200, polyethylene glycol 400, propylene glycol), and short chain alcohols (ethanol, propanol, butanol and octanol) were also screened similarly. Tween 80 and butanol were selected as emulsifier and co-emulsifier respectively to formulate nano-emulsion by aqueous titration method. However, separation was observed after 24 hours. Therefore, span 80 was added as an auxiliary emulsifier to improve emulsification efficiency. Finally, a blend of tween 80, span 80 and butanol was optimized as emulsifier (56 % wt/wt) to emulsify 9 % wt/wt of olive oil in 33 % wt/wt water. Pseudo-ternary phase diagram was employed to identify and optimize the components. Optimized formulation based on phase separation and thermokinetic stability was characterized for globule size, size distribution, zeta potential, viscosity, refractive index and pH. Globule size analysis by zetasizer nano ZS was further confirmed by transmission electron microscopy. Permeation flux of fluconazole from optimized formulation through artificial skin was approximately three fold higher than the control. In conclusion, developed olive oil based nano-emulsion of fluconazole demonstrated promising solubility, permeability and stability. Keywords: Fluconazole, olive oil, nano-emulsion, transdermal permeatio

Development and Characterization of Sustained-Released Donepezil Hydrochloride Solid Dispersions Using Hot Melt Extrusion Technology

The aim of this work was to develop the sustained release formulation of donepezil hydrochloride (DH) using the hot-melt extruded solid dispersion technique via the rational screening of hydrophobic carriers. Hydrophobic carriers with different physicochemical properties such as pH-independent swellability, low-permeability (Eudragit® RS PO (E-RS)), pH-independent non-swellability (ethyl cellulose N7 (EC-N7)), and the presence of lipids (Compritol® 888 ATO (C-888)) with or without pore-forming agents were used to achieve the sustained release profile of DH. Mannitol (MNT) was chosen as the temporary pore-forming agent. The thermal analysis showed that both the drug and C-888 preserved their crystallinity within a solid dispersion. During a dissolution test, MNT could generate pores, and the drug release rate was proportionally correlated to the MNT content. Tailoring of the ratio of C-888 and MNT in the formulations along with an appropriate extrusion temperature profile resulted in the modified release of DH, and a preferable release pattern was obtained under these conditions. C-888 was chosen for the further investigations to obtain tablets with a high integrity. The optimized tablets were compared to the marketed formulation of Aricept® in terms of drug release profiles. The optimized formulation showed the stable and sustained release behavior of extended release profile, which was close to the release behavior of Aricept® with good tablet characteristics. It was concluded that the hot-melt extrusion technique can be utilized for the manufacturing of DH sustained release tablets with improved tablet integrity and characteristics by co-processing the tablet excipient with DH/C-888

Effect of Lutrol\u3csup\u3e®\u3c/sup\u3e F grades (poloxamer) on dissolution of Hot-melt extruded Kollidon\u3csup\u3e®\u3c/sup\u3e VA64-felodipine matrices

The objective of this study was to assess the potential of Lutrol® F grades as polymeric surfactants for dissolution enhancement of Kollidon®VA64-drug matrices produced by hot-melt extrusion (HME). The poorly soluble model drug felodipine (FEL) with a medium melting point was selected for this study. Two different grades of Lutrol® F (also called Kolliphor® P grades) were added into the HME systems to investigate their influence on the drug-incorporated matrices. Two grades of Lutrols i.e., Lutrol® F 68 (Kolliphor®P 188) and Lutrol® F 127 (Kolliphor®P 407) were studied as polymeric solubilizers. FEL was mixed with Kollidon®VA64, with or without Lutrol®F (alone or in combination) at predetermined amounts which resulted in 8 different formulations. Each blend was melt-extruded at the same extrusion conditions. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses were performed to evaluate their physicochemical properties. DSC and PXRD studies suggested the formation of amorphous solid dispersion for all extruded formulations. Dissolution studies revealed that the extrudates with Lutrol® F grades exhibited faster and higher release compared to formulations without Lutrol® F grades. Formulations with high drug loading, which did not include Lutrol® F grades, demonstrated low drug release profiles when compared with the same formulations containing Lutrol® F grades. Fourier transform infrared (FTIR) studies suggested that a stronger hydrogen bond has occurred between the (-NH) of FEL and (C=O) of the pyrrolidone group in Kollidon® VA 64. Overall, these studies suggested the potential of Lutrols in enhancing the dissolution rate of poorly soluble model drug FEL

Development and Characterization of Sustained-Released Donepezil Hydrochloride Solid Dispersions Using Hot Melt Extrusion Technology

The aim of this work was to develop the sustained release formulation of donepezil hydrochloride (DH) using the hot-melt extruded solid dispersion technique via the rational screening of hydrophobic carriers. Hydrophobic carriers with different physicochemical properties such as pH-independent swellability, low-permeability (Eudragit® RS PO (E-RS)), pH-independent non-swellability (ethyl cellulose N7 (EC-N7)), and the presence of lipids (Compritol® 888 ATO (C-888)) with or without pore-forming agents were used to achieve the sustained release profile of DH. Mannitol (MNT) was chosen as the temporary pore-forming agent. The thermal analysis showed that both the drug and C-888 preserved their crystallinity within a solid dispersion. During a dissolution test, MNT could generate pores, and the drug release rate was proportionally correlated to the MNT content. Tailoring of the ratio of C-888 and MNT in the formulations along with an appropriate extrusion temperature profile resulted in the modified release of DH, and a preferable release pattern was obtained under these conditions. C-888 was chosen for the further investigations to obtain tablets with a high integrity. The optimized tablets were compared to the marketed formulation of Aricept® in terms of drug release profiles. The optimized formulation showed the stable and sustained release behavior of extended release profile, which was close to the release behavior of Aricept® with good tablet characteristics. It was concluded that the hot-melt extrusion technique can be utilized for the manufacturing of DH sustained release tablets with improved tablet integrity and characteristics by co-processing the tablet excipient with DH/C-888

Product Development Studies of Cranberry Seed Oil Nanoemulsion

Cranberry seed oil (CSO) can be used in various skin diseases, perhaps due to the presence of ω-3, ω-6, and ω-9 fatty acids. In addition, tocotrienols (vitamin E) has demonstrated powerful antioxidant activity. The combined application of CSO nanoemulsions open a promising avenue for skin conditions. The goal of this work was to create a nanoemulsion (NE) containing CSO and test its stability and in vitro release. To make NE formulations (CNE1-CNE6), the aqueous titration method was used. Following the creation of NE formulations, we selected the CNE4 formulation, which had a mean droplet size of around 110 nm, a narrow size distribution (PDI < 0.2), a steady zeta potential (−34.21 mV), and a high percentage transmittance (>99%). Furthermore, electron microscopy imaging revealed nanosized spherical droplets without any aggregation in the CNE4 formulation, which showed high entrapment efficiency (>80%). Densitometry analysis confirmed linoleic acid (RF 0.62) as a major component of CSO using toluene–acetone–glacial acetic acid (90:9:1 v/v/v) as a mobile phase. Nanogel had a three-fold greater cumulative drug permeation through the skin than neat CSO. This study shows that a unique CSO delivery technique can be used to treat skin diseases

Combining the dual antibacterial and regenerative activities of platelet-rich plasma with β-lactams to mitigate MRSA-infected skin wounds

The emergence of multidrug-resistant bacteria contributes to the necessity of developing novel infection treatment approaches. This study was designed to evaluate the antimicrobial and wound healing activities of platelet-rich plasma (PRP) in combination with β-lactams (ampicillin and/or oxacillin) for the application on methicillin-resistant Staphylococcus aureus (MRSA)-infected skin. PRP was collected from the peripheral blood of healthy donors. The anti-MRSA activity was tested through a growth inhibition curve, colony-forming unit (CFU), and SYTO 9 assay. The PRP incorporation lowered the minimum inhibitory concentration (MIC) of ampicillin and oxacillin against MRSA. The combination of β-lactams together with PRP showed a three-log CFU reduction of MRSA. The major components of PRP for eliminating MRSA were found to be the complement system and iron sequestration proteins, according to the proteomic analysis. The adhesive bacterial colony in the microplate was decreased from 2.9 × 107 to 7.3 × 105 CFU after the treatment of cocktails containing β-lactams and PRP. The cell-based study indicated that keratinocyte proliferation was stimulated by PRP. The in vitro scratch and transwell experiments revealed that PRP improved keratinocyte migration. In the MRSA-infected mouse skin model, PRP appeared to show a synergistic effect for wound area reduction by 39% when combined with β-lactams. The MRSA burden in the infected area was lessened two-fold after topical administration of the combined β-lactams and PRP. PRP inhibited macrophage infiltration in the wound site to shorten the inflammatory phase and accelerate the initiation of the proliferative phase. No skin irritation was detected with the topical delivery of this combination. Our findings suggested that β-lactams plus PRP was applicable to alleviate the problems associated with MRSA via dual antibacterial and regenerative activities

Hepatoprotective Effects of Bioflavonoid Luteolin Using Self-Nanoemulsifying Drug Delivery System

Luteolin (LUT) is a natural pharmaceutical compound that is weakly water soluble and has low bioavailability when taken orally. As a result, the goal of this research was to create self-nanoemulsifying drug delivery systems (SNEDDS) for LUT in an attempt to improve its in vitro dissolution and hepatoprotective effects, resulting in increased oral bioavailability. Using the aqueous phase titration approach and the creation of pseudo-ternary phase diagrams with Capryol-PGMC (oil phase), Tween-80 (surfactant), and Transcutol-HP (co-emulsifier), various SNEDDS of LUT were generated. SNEDDS were assessed for droplet size, polydispersity index (PDI), zeta potential (ZP), refractive index (RI), and percent of transmittance (percent T) after undergoing several thermodynamic stability and self-nanoemulsification experiments. When compared to LUT suspension, the developed SNEDDS revealed considerable LUT release from all SNEDDS. Droplet size was 40 nm, PDI was <0.3, ZP was −30.58 mV, RI was 1.40, percent T was >98 percent, and drug release profile was >96 percent in optimized SNEDDS of LUT. For in vivo hepatoprotective testing in rats, optimized SNEDDS was chosen. When compared to LUT suspension, hepatoprotective tests showed that optimized LUT SNEDDS had a substantial hepatoprotective impact. The findings of this investigation suggested that SNEDDS could improve bioflavonoid LUT dissolution rate and therapeutic efficacy

Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepared by different techniques

Apigenin (APG) is a poorly soluble bioactive compound/nutraceutical which shows poor bioavailability upon oral administration. Hence, the objective of this research work was to develop APG solid dispersions (SDs) using different techniques with the expectation to obtain improvement in its in vitro dissolution rate and in vivo bioavailability upon oral administration. Different SDs of APG were prepared by microwave, melted and kneaded technology using pluronic-F127 (PL) as a carrier. Prepared SDs were characterized using “thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) spectrometer, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM)”. After characterization, prepared SDs of APG were studied for in vitro drug release/dissolution profile and in vivo pharmacokinetic studies. The results of TGA, DSC, FTIR, PXRD and SEM indicated successful formation of APG SDs. In vitro dissolution experiments suggested significant release of APG from all SDs (67.39–84.13%) in comparison with control (32.74%). Optimized SD of APG from each technology was subjected to in vivo pharmacokinetic study in rats. The results indicated significant improvement in oral absorption of APG from SD prepared using microwave and melted technology in comparison with pure drug and commercial capsule. The enhancement in oral bioavailability of APG from microwave SD (319.19%) was 3.19 fold as compared with marketed capsule (100.00%). Significant enhancement in the dissolution rate and oral absorption of APG from SD suggested that developed SD systems can be successfully used for oral drug delivery system of APG. Keywords: Apigenin, Microwave technology, Pluronic-F127, Solid dispersion, Bioavailabilit